Cancer is a major cause of illness and death worldwide. It is the leading cause of human mortality exceeded only by cardiovascular diseases (Evangelia D. C. et. al. Bioorg. Med. Chem., 2005, 13, 765-72). Cancer occurs in a wide range of tissues with different outcomes. Approximately 200 different types of cancers are reported with lung, breast, prostate and colon cancer accounting for the majority of deaths (cancerresearchuk.org). Cancer arises from an accumulation of genetic and epigenetic alterations within proto-oncogenes and tumour suppressor genes leading to the deregulation of the tightly controlled signaling pathways (Smith S. C. et. al. Nat Rev Cancer., 2009, 9, 253-264; Grady W. M. et. al. Gastroenterology, 2008, 135, 1079-99). Abnormal signaling cascades breakdown the cell cycle and produce genomic and chromosomal instability (Malumbres M. et. al. Nat Rev Cancer., 2009, 9, 153-166; Stratton M. R. et. al. Nature., 2009, 458, 719-24). Subsequently, normal cells lose control over their growth and forms primary tumors. In later stages, cancerous cells metastasize from the primary tumours to distant organs in the body and it is difficult to treat the cancer at this stage (Klein C. A. et. al. Nat Rev Cancer., 2009, 9, 302-12). Chemotherapy and radiation therapies are two widely used therapeutic options for the treatment of cancer. These techniques effectively block the tumor growth but traditionally prescribed chemotherapeutic agents have problems with toxicity and drug resistance (Urruticoechea A. et. al. Current Pharmaceutical Design, 2010, 16, 3-10). Although, numerous kinase inhibitors have been discovered recently and several have been successfully developed, including Gleevec, (Robert R. Jr. Biochem Biophys Res Commun, 2003, 309, 709-17) Iressa, (Nutt J. E. et. al. J. Br. J. Cancer., 2004, 8, 1679-85) Tarceva, (Dowell J. et. al. Nat. Rev. Drug Disc., 2005, 4, 13-14) and Tykerb (Moy B. et. al. Oncologist., 2006, 10, 1047-57) there is still a strong demand for discovery of more efficacious and less toxic anticancer agents. Other anti-cancer targets that have been realized recently are human DNA ligases. The potential of targeting ligases arises from the fact that they are indispensible in all DNA replication and repair processes in the body, processes that are already targeted the most in chemotherapy. Inhibiting ligases lead to accumulation of strand breaks in the cells that are lethal at high concentrations. Reports also conform that the levels of DNA ligases are higher in cancer cells compared to normal cells that do not replicate all the time. We have recently published a review citing all known ligase inhibitors and reviewed all the methods by which ligases maybe targeted and their functions maybe inhibited (Singh D. K. et. al. Med Res Rev., 2013 DOI 10.1002/med.21298).
Molecular hybridization is a new concept useful for the design and development of novel biologically active molecules. Above paradigm produce a new hybrid compounds based on the combination of pharmacophoric moieties of different bioactive substances with improved affinity and efficacy, when compared to the parent compounds (Sashidhara K. V. et. al. J. Med. Chem., 2012, 55, 2769-79). This strategy has resulted in compounds with modified selectivity profile, different and/or dual modes of action and reduced undesired side effects (Meunier B. Acc Chem Res., 2008, 41, 69-77). Cationic lipid conjugated small molecules are emerging hybrid molecules. Upon cationic lipid modifications, biologically active compounds whether natural or synthetic, show improved anticancer activities with different modes of action.
Using this lucrative lipid hybridization strategy recently various cationic lipidated small molecules with improved activity have been reported including, cationic lipid-haloperidol hybrids (Banerjee R. et. al. J. Med. Chem., 2011, 54, 2378-90) and cationic lipidated emodins (Wang et. al. Eur. J. Med. Chem., 2012, 56, 320-31). Above reports give the impression that the cationic lipid conjugation enhances anticancer activity of the small molecules but the crucial point to be noted is that the improved activity is highly dependent on the small molecule portion and that too is highly chain length specific. Here we would like to reveal an important point that not all the combinations of small molecules and carbon chain lengths associated with cationic lipids produces anticancer property, there needs to be a specific combination in order to generate potential anticancer agents. The whole picture can be explained from the example of estradiol that has strong compatibility with only eight chain length containing cationic lipid [Mol. Cancer Res., 2011, 9, 364-374], whereas benzamide has best compatibility with only ten chain length cationic moiety [Eur. J. Med. Chem., 2012, 56, 400-408] in order to elicit the selective anticancer activity. Best on the mentioned examples, one cannot simply generalize that cationic lipid moiety enhances the activity of all small molecules.
Inspired by these encouraging results, in order to further explore the structure-activity relationship (SAR) of the cationic lipid portion, we envisioned the construction of cationic lipo-cordiarimide A hybrids as shown in FIG. 1. The rationale behind the selection of ‘cordiarimide A’ is it is a glutarimide natural product and recently isolated from the roots of Cordia globifera (Parks J. et. al. J. Nat. Prod., 2010, 73, 992). Glutarimide's are reported to have antibacterial, antitumoral, anti-inflammatory, and other pharmacological activities (Decker S. et. al. Ann. N.Y. Acad Sci., 2005, 1059, 61-9). Thalidomide and Lenalidomide are the most well known drugs among glutarimide derivatives.
In the present invention we report the design, synthesis, anticancer activity and DNA ligase-1 inhibitory potential of novel cationic lipid modified cordiarimides.